DOCSLIB.ORG

Integrative Analysis of Head and Neck Cancer Identifies Two Biologically Distinct HPV and Three Non-HPV Subtypes

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Integrative Analysis of Head and Neck Cancer Identifies Two Biologically Distinct HPV and Three Non-HPV Subtypes Author Manuscript Published OnlineFirst on December 9, 2014; DOI: 10.1158/1078-0432.CCR-14-2481 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Running title: Integrative analysis identifies five distinct HNC subtypes Integrative analysis of Head and Neck Cancer identifies two biologically distinct HPV and three non-HPV subtypes Michaela K. Keck1,2†, Zhixiang Zuo1†, Arun Khattri1†, Thomas P. Stricker3, Christopher Brown7, Matin Imanguli4, Damian Rieke1, Katharina Endhardt1, Petra Fang1, Johannes Brägelmann1, Rebecca DeBoer1, Mohamed El-Dinali1, Serdal Aktolga1, Zhengdeng Lei5, Patrick Tan5,6, Steve G. Rozen5, Ravi Salgia1,11, Ralph R. Weichselbaum1,11, Mark W. Lingen3,11, 8 12 9 10,11 1,11 Michael D. Story , Kie Kian Ang , Ezra E.W. Cohen , Kevin P. White , Everett E. Vokes , Tanguy Y. Seiwert1,10,11* 1The University of Chicago, Department of Medicine, Chicago, IL, USA. 2The University of Hohenheim, Institute of Biological Chemistry and Nutrition, Stuttgart, Germany. 3The University of Chicago, Department of Pathology, Chicago, IL, USA. 4The University of Texas Southwestern Medical Center, Department of Otolaryngology-Head and Neck Surgery, Dallas, TX, USA. 5Duke-NUS Graduate Medical School, Singapore. 6Genome Institute of Singapore, Singapore. 7The University of Chicago, Department of Human Genetics, Chicago, IL, USA. 8The University of Texas, Southwestern Medical Center, Department of Radiation Oncology, Dallas, TX, USA. 9University of California San Diego, La Jolla, CA 10The University of Chicago, Institute for Genomics and Systems Biology, Chicago, IL, USA. 11The University of Chicago Comprehensive Cancer Center, Chicago, IL, USA. 12 The University of Texas, MD Anderson Cancer Center, Houston, TX, USA. † Authors contributed equally Keywords: Head and Neck Cancer; Integrated Genomic Analysis; Human papillomavirus; Immune Phenotype, HER signaling, oligoclonal T-cell infiltration Financial Support: This work was supported by an ASCO Translational Professorship (EEV). We would like to thank the Achatz Research Fund for its support of HNC research. Dr. Seiwert was supported by The Flight Attendant Medical Research Institute (FAMRI) Young Investigator Award. *Corresponding Author Address: Tanguy Seiwert Knapp Center for Biomedical Discovery at the University of Chicago 900 E. 57th Street, 7110 Chicago, IL 60637 United States Tel: 773-702-2452 Fax: 773-702-3002 Email: [email protected] Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2014 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 9, 2014; DOI: 10.1158/1078-0432.CCR-14-2481 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. The authors disclose no potential conflict of interest. Word count (excluding references): 3731 Number of figures and tables: 6 Statement of Translational Relevance: Head and Neck Cancer (HNC) is comprised of HPV(+) and HPV(-) tumors. However there remains significant heterogeneity in clinical behavior (e.g. response to therapies including anti- EGFR or anti-PD-1 immunotherapy) and further biologic sub-classification and elucidation of specific biologic characteristics is lacking. One limitation of available classifications is the absence of any larger (and representative) cohort of HPV(+) tumors or the lack of validation across multiple datasets/platforms. We identify five HNC subtypes including two distinct HPV-subtypes with differential biology across multiple HNC cohorts, and show validity of subtypes and associated biology across all currently available HNC datasets including the TCGA HNC cohort: In particular we report 1) an immune (and mesenchymal) phenotype present in a group of HNC tumors independent of HPV- status, 2) a group with non-HPV-associated tumors showing a prominent HER-driven phenotype as well as hypoxia, which are candidate biomarkers for respective therapies (e.g. PD-1, EGFR/HER, or hypoxia-targeting agents). 2 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2014 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 9, 2014; DOI: 10.1158/1078-0432.CCR-14-2481 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract: Purpose: Current classification of head and neck squamous cell carcinomas (HNSCC) based on anatomic site and stage fails to capture biologic heterogeneity or adequately inform treatment. Experimental Design: Here we use gene expression based consensus clustering, copy number profiling, and HPV-status on a clinically homogenous cohort of 134 locoregionally-advanced HNSCCs with 44% HPV(+) tumors together with additional cohorts, which in total comprise 938 tumors, to identify HNSCC subtypes and discover several subtype-specific, translationally relevant characteristics. Results: We identified five subtypes of HNSCC including two biologically distinct HPV subtypes. One HPV(+) and one HPV(-) subtype show a prominent immune and mesenchymal phenotype. Prominent tumor infiltration with CD8+ lymphocytes characterizes this inflamed/mesenchymal subtypes - independent of HPV status. Compared to other subtypes, the two HPV subtypes show low expression and no copy number events for EGFR/HER-ligands and absence of EGFR/HER-ligand expression. By contrast the Basal subtype is uniquely characterized by a prominent EGFR/HER signaling phenotype driven by multiple HER ligands, as well as strong hypoxic differentiation not seen in other subtypes. Conclusion: Our five-subtype classification provides a comprehensive overview of HPV(+) as well as HPV(-) HNSCC biology with significant translational implications for biomarker development and personalized care for HNSCC patients. 3 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2014 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 9, 2014; DOI: 10.1158/1078-0432.CCR-14-2481 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction Head and neck squamous cell carcinoma (HNSCC) is the sixth most common non-skin cancer worldwide with an annual incidence of ~600,000 cases and a mortality rate of 40-50% (1,2). The major known risk factors are environmental exposures to tobacco products, alcohol, and infection with high-risk human papillomaviruses (HPV). The incidence of HPV(+) tumors is rising rapidly and HPV status is now the strongest prognostic marker (3). While HNSCC is now widely viewed as comprised of two distinct clinical entities, HPV(+) and HPV(-), a therapeutically relevant molecular classification system remains elusive. Prior attempts at profiling this clinically heterogeneous disease have been hampered by lack of information about HPV status and/or absence of significant numbers of HPV(+) cases, small sample size, and lack of annotation (4,5). Currently, neither molecular classification nor validated biomarkers are used in clinical practice. Instead all HNSCC patients are treated independent of the underlying biology based on stage and anatomic location, typically using a combination of surgery, radiation, and chemotherapy (6). Cetuximab, an anti-EGFR antibody, is the only approved targeted therapy for HNSCC, but predictive biomarkers remain to be identified and overall cetuximab has a response rate of 7-13% (7). In the current study, we investigate a fully clinically annotated, very homogenous patient cohort of locoregionally advanced HNSCC (including 44% HPV(+) tumors) all treated uniformly with organ-preserving chemoradiotherapy together with all available other HNC cohorts including the Cancer Genome Atlas (TCGA) head and neck cohort, in order to identify HNSCC subtypes and their biologic and prognostic characteristics. We integrate gene expression based consensus clustering, cross-platform approaches for validation, copy number profiling, and HPV status in order to discover subtype-specific, translationally relevant biology. 4 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2014 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 9, 2014; DOI: 10.1158/1078-0432.CCR-14-2481 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. The resulting new taxonomy of HNSCC closely correlates with multiple HNC-relevant oncogenic processes and a biology based taxonomy of HNSCC. In particular we identify two subtypes of HPV(+) head and neck cancer, and two subtypes (one HPV(+), one HPV(-)) with a prominent immune phenotype characterized by CD8+ T-cell infiltration, as well as a subtype with near exclusive HER ligand/EGFR copy number driven signaling. As such our classification is broadly applicable to biomarker and therapy development for head and neck cancer and will inform future clinical and preclinical studies, biomarker development, and personalized HNC care. 5 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2014 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 9, 2014; DOI: 10.1158/1078-0432.CCR-14-2481 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Materials and Methods Patient Samples OCT blocks of frozen tissue samples were obtained from the University of Chicago Head and Neck Cancer tissue bank (IRB approved protocol UCCCC#8980)(Supplemental
Load more

Recommended publications
  • The P16 (Cdkn2a/Ink4a) Tumor-Suppressor Gene in Head
    The p16 (CDKN2a/INK4a) Tumor-Suppressor Gene in Head and Neck Squamous Cell Carcinoma: A Promoter Methylation and Protein Expression Study in 100 Cases Lingbao Ai, M.D., Krystal K. Stephenson, Wenhua Ling, M.D., Chunlai Zuo, M.D., Perkins Mukunyadzi, M.D., James Y. Suen, M.D., Ehab Hanna, M.D., Chun-Yang Fan, M.D., Ph.D. Departments of Pathology (LA, KKS, CZ, PM, CYF) and Otolaryngology-Head and Neck Surgery (CYF, JYS, EH), University of Arkansas for Medical Sciences; and School of Public Health (LA, WL), Sun-Yat Sen University, Guangzhou, China apparent loss of p16 protein expression appears to The p16 (CDKN2a/INK4a) gene is an important be an independent prognostic factor, although loss tumor-suppressor gene, involved in the p16/cyclin- of p16 protein may be used to predict overall pa- dependent kinase/retinoblastoma gene pathway of tient survival in early-stage head and neck squa- cell cycle control. The p16 protein is considered to mous cell carcinoma. be a negative regulator of the pathway. The gene encodes an inhibitor of cyclin-dependent kinases 4 KEY WORDS: Gene inactivation, Head and and 6, which regulate the phosphorylation of reti- neck squamous cell carcinoma, p16, Promoter noblastoma gene and the G1 to S phase transition of hypermethylation. the cell cycle. In the present study, p16 gene pro- Mod Pathol 2003;16(9):944–950 moter hypermethylation patterns and p16 protein expression were analyzed in 100 consecutive un- The development of head and neck squamous cell treated cases of primary head and neck squamous carcinoma is believed to be a multistep process, in cell carcinoma by methylation-specific PCR and im- which genetic and epigenetic events accumulate as munohistochemical staining.
    [Show full text]
  • Involvement of the Cyclin-Dependent Kinase Inhibitor P16 (Ink4a) in Replicative Senescence of Normal Human Fibroblasts
    Proc. Natl. Acad. Sci. USA Vol. 93, pp. 13742–13747, November 1996 Biochemistry Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts DAVID A. ALCORTA*†,YUE XIONG‡,DAWN PHELPS‡,GREG HANNON§,DAVID BEACH§, AND J. CARL BARRETT* *Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709; ‡Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599; and §Howard Hughes Medical Institute, Cold Spring Harbor Laboratories, Cold Spring Harbor, NY 11724 Communicated by Raymond L. Erickson, Harvard University, Cambridge, MA, September 19, 1996 (received for review on May 15, 1996) ABSTRACT Human diploid fibroblasts (HDFs) can be viewed in ref. 5). In senescent fibroblasts, CDK2 is catalytically grown in culture for a finite number of population doublings inactive and the protein down-regulated (7). CDK4 is also before they cease proliferation and enter a growth-arrest state reported to be down-regulated in senescent cells (8), while the termed replicative senescence. The retinoblastoma gene prod- status of CDK6 has not been previously addressed. The uct, Rb, expressed in these cells is hypophosphorylated. To activating cyclins for these CDKs, cyclins D1 and E, are present determine a possible mechanism by which senescent human in senescent cells at similar or elevated levels relative to early fibroblasts maintain a hypophosphorylated Rb, we examined passage cells (8). A role of the CDK inhibitors in senescence the expression levels and interaction of the Rb kinases, CDK4 was revealed by the isolation of a cDNA of a highly expressed and CDK6, and the cyclin-dependent kinase inhibitors p21 message in senescent cells that encoded the CDK inhibitor, p21 and p16 in senescent HDFs.
    [Show full text]
  • Transcriptional Regulation of the P16 Tumor Suppressor Gene
    ANTICANCER RESEARCH 35: 4397-4402 (2015) Review Transcriptional Regulation of the p16 Tumor Suppressor Gene YOJIRO KOTAKE, MADOKA NAEMURA, CHIHIRO MURASAKI, YASUTOSHI INOUE and HARUNA OKAMOTO Department of Biological and Environmental Chemistry, Faculty of Humanity-Oriented Science and Engineering, Kinki University, Fukuoka, Japan Abstract. The p16 tumor suppressor gene encodes a specifically bind to and inhibit the activity of cyclin-CDK specific inhibitor of cyclin-dependent kinase (CDK) 4 and 6 complexes, thus preventing G1-to-S progression (4, 5). and is found altered in a wide range of human cancers. p16 Among these CKIs, p16 plays a pivotal role in the regulation plays a pivotal role in tumor suppressor networks through of cellular senescence through inhibition of CDK4/6 activity inducing cellular senescence that acts as a barrier to (6, 7). Cellular senescence acts as a barrier to oncogenic cellular transformation by oncogenic signals. p16 protein is transformation induced by oncogenic signals, such as relatively stable and its expression is primary regulated by activating RAS mutations, and is achieved by accumulation transcriptional control. Polycomb group (PcG) proteins of p16 (Figure 1) (8-10). The loss of p16 function is, associate with the p16 locus in a long non-coding RNA, therefore, thought to lead to carcinogenesis. Indeed, many ANRIL-dependent manner, leading to repression of p16 studies have shown that the p16 gene is frequently mutated transcription. YB1, a transcription factor, also represses the or silenced in various human cancers (11-14). p16 transcription through direct association with its Although many studies have led to a deeper understanding promoter region.
    [Show full text]
  • The P16 Status of Tumor Cell Lines Identifies Small Molecule Inhibitors Specific for Cyclin-Dependent Kinase 41
    Vol. 5, 4279–4286, December 1999 Clinical Cancer Research 4279 The p16 Status of Tumor Cell Lines Identifies Small Molecule Inhibitors Specific for Cyclin-dependent Kinase 41 Akihito Kubo,2 Kazuhiko Nakagawa,2, 3 CDK4 kinase inhibitors that may selectively induce growth Ravi K. Varma, Nicholas K. Conrad, inhibition of p16-altered tumors. Jin Quan Cheng, Wen-Ching Lee, INTRODUCTION Joseph R. Testa, Bruce E. Johnson, INK4A 4 The p16 gene (also known as CDKN2A) encodes p16 , Frederic J. Kaye, and Michael J. Kelley which inhibits the CDK45:cyclin D and CDK6:cyclin D com- Medicine Branch [A. K., K. N., N. K. C., F. J. K., B. E. J.] and plexes (1). These complexes mediate phosphorylation of the Rb Developmental Therapeutics Program [R. K. V.], National Cancer Institute, Bethesda, Maryland 20889; Department of Medical protein and allow cell cycle progression beyond the G1-S-phase Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania checkpoint (2). Alterations of p16 have been described in a wide 19111 [J. Q. C., W-C. L., J. R. T.]; and Department of Medicine, variety of histological types of human cancers including astro- Duke University Medical Center, Durham, North Carolina 27710 cytoma, melanoma, leukemia, breast cancer, head and neck [M. J. K.] squamous cell carcinoma, malignant mesothelioma, and lung cancer. Alterations of p16 can occur through homozygous de- ABSTRACT letion, point mutation, and transcriptional suppression associ- ated with hypermethylation in cancer cell lines and primary Loss of p16 functional activity leading to disruption of tumors (reviewed in Refs. 3–5). the p16/cyclin-dependent kinase (CDK) 4:cyclin D/retino- Whereas the Rb gene is inactivated in a narrow range of blastoma pathway is the most common event in human tumor cells, the pattern of mutational inactivation of Rb is tumorigenesis, suggesting that compounds with CDK4 ki- inversely correlated with p16 alterations (6–8), suggesting that nase inhibitory activity may be useful to regulate cancer cell a single defect in the p16/CDK4:cyclin D/Rb pathway is suffi- growth.
    [Show full text]
  • AP-1 in Cell Proliferation and Survival
    Oncogene (2001) 20, 2390 ± 2400 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc AP-1 in cell proliferation and survival Eitan Shaulian1 and Michael Karin*,1 1Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, California, CA 92093-0636, USA A plethora of physiological and pathological stimuli extensively discussed previously (Angel and Karin, induce and activate a group of DNA binding proteins 1991; Karin, 1995). that form AP-1 dimers. These proteins include the Jun, The mammalian AP-1 proteins are homodimers and Fos and ATF subgroups of transcription factors. Recent heterodimers composed of basic region-leucine zipper studies using cells and mice de®cient in individual AP-1 (bZIP) proteins that belong to the Jun (c-Jun, JunB proteins have begun to shed light on their physiological and JunD), Fos (c-Fos, FosB, Fra-1 and Fra-2), Jun functions in the control of cell proliferation, neoplastic dimerization partners (JDP1 and JDP2) and the closely transformation and apoptosis. Above all such studies related activating transcription factors (ATF2, LRF1/ have identi®ed some of the target genes that mediate the ATF3 and B-ATF) subfamilies (reviewed by (Angel eects of AP-1 proteins on cell proliferation and death. and Karin, 1991; Aronheim et al., 1997; Karin et al., There is evidence that AP-1 proteins, mostly those that 1997; Liebermann et al., 1998; Wisdom, 1999). In belong to the Jun group, control cell life and death addition, some of the Maf proteins (v-Maf, c-Maf and through their ability to regulate the expression and Nrl) can heterodimerize with c-Jun or c-Fos (Nishiza- function of cell cycle regulators such as Cyclin D1, p53, wa et al., 1989; Swaroop et al., 1992), whereas other p21cip1/waf1, p19ARF and p16.
    [Show full text]
  • Expression of P16 INK4A and P14 ARF in Hematological Malignancies
    Leukemia (1999) 13, 1760–1769 1999 Stockton Press All rights reserved 0887-6924/99 $15.00 http://www.stockton-press.co.uk/leu Expression of p16INK4A and p14ARF in hematological malignancies T Taniguchi1, N Chikatsu1, S Takahashi2, A Fujita3, K Uchimaru4, S Asano5, T Fujita1 and T Motokura1 1Fourth Department of Internal Medicine, University of Tokyo, School of Medicine; 2Division of Clinical Oncology, Cancer Chemotherapy Center, Cancer Institute Hospital; 3Department of Hematology, Showa General Hospital; 4Third Department of Internal Medicine, Teikyo University, School of Medicine; and 5Department of Hematology/Oncology, Institute of Medical Science, University of Tokyo, Tokyo, Japan The INK4A/ARF locus yields two tumor suppressors, p16INK4A tumor suppressor genes.10,11 In human hematological malig- ARF and p14 , and is frequently deleted in human tumors. We nancies, their inactivation occurs mainly by means of homo- studied their mRNA expressions in 41 hematopoietic cell lines and in 137 patients with hematological malignancies; we used zygous deletion or promoter region hypermethylation a quantitative reverse transcription-PCR assay. Normal periph- (reviewed in Ref. 12). In tumors such as pancreatic adenocar- eral bloods, bone marrow and lymph nodes expressed little or cinomas, esophageal squamous cell carcinomas and familial undetectable p16INK4A and p14ARF mRNAs, which were readily melanomas, p16INK4A is often inactivated by point mutation, detected in 12 and 17 of 41 cell lines, respectively. Patients with 12 INK4A which is not the case in hematological malignancies. On hematological malignancies frequently lacked p16 INK4C INK4D ARF the other hand, genetic aberrations of p18 or p19 expression (60/137) and lost p14 expression less frequently 12 (19/137, 13.9%).
    [Show full text]
  • Uncommon Association of Germline Mutations of RET Proto-Oncogene
    European Journal of Endocrinology (2008) 158 417–422 ISSN 0804-4643 CASE REPORT Uncommon association of germline mutations of RET proto-oncogene and CDKN2A gene L Foppiani1, F Forzano2, I Ceccherini3, W Bruno4, P Ghiorzo4, F Caroli3, P Quilici5, R Bandelloni5, A Arlandini6, G Sartini6, M Cabria7 and P Del Monte1 1Endocrinology 2Genetics Laboratory, Galliera Hospital, 16128 Genova, Italy, 3Laboratory of Molecular Genetics, G Gaslini Institute, 16148 Genova, Italy, 4Department of Oncology, Biology and Genetics/Medical Genetics Service, University of Genova, 1632 Genova, Italy, 5Pathology Unit, 6Division of Surgery and 7Nuclear Medicine, Galliera Hospital, 16128 Genova, Italy (Correspondence should be addressed to L Foppiani who is now at S S D Endocrinologia, Mura delle Cappuccine 14, 16128 Genova, Italy; Email: [email protected]) Abstract Introduction: Calcitonin measurement is advised in the diagnosis of thyroid nodules, as it is an accurate marker of medullary thyroid carcinoma (MTC). C-cell hyperplasia (CCH)-induced hypercalcitoninemia cannot be distinguished from that induced by MTC, unless surgery is performed. Case: We report the clinical and biological features of a patient with a family history of cancer, including melanoma and pancreatic cancer, who had previously undergone surgery for melanoma. He presented the unusual association of papillary thyroid carcinoma (PTC), normocalcemic hyperpara- thyroidism, and hypercalcitoninemia with a pathological response to pentagastrin, which was histologically deemed secondary to CCH. Multiple endocrine neoplasia (MEN) 2A was diagnosed. RET gene analysis showed a p.V804M missense mutation in exon 14, a low- but variably penetrant defect found in both sporadic and MEN2A-associated MTC/CCH, and a p.G691S polymorphism in exon 11.
    [Show full text]
  • MYC Oncogene Contributions to Release of Cell Cycle Brakes
    Review MYC Oncogene Contributions to Release of Cell Cycle Brakes Lucía García-Gutiérrez 1,2, María Dolores Delgado 1 and Javier León 1* 1 Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC) CSIC-Universidad de Cantabria and Department of Biología Molecular, Universidad de Cantabria, 39011 Santander, Spain; [email protected] (M.D.D.) 2 Current address: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland; [email protected] (L.G-G) * Correspondence: [email protected]; Tel: +34-942-201952 Received: 24 February 2019; Accepted: 18 March 2019; Published: 22 March 2019 Abstract: Promotion of the cell cycle is a major oncogenic mechanism of the oncogene c-MYC (MYC). MYC promotes the cell cycle by not only activating or inducing cyclins and CDKs but also through the downregulation or the impairment of the activity of a set of proteins that act as cell- cycle brakes. This review is focused on the role of MYC as a cell-cycle brake releaser i.e., how MYC stimulates the cell cycle mainly through the functional inactivation of cell cycle inhibitors. MYC antagonizes the activities and/or the expression levels of p15, ARF, p21, and p27. The mechanism involved differs for each protein. p15 (encoded by CDKN2B) and p21 (CDKN1A) are repressed by MYC at the transcriptional level. In contrast, MYC activates ARF, which contributes to the apoptosis induced by high MYC levels. At least in some cells types, MYC inhibits the transcription of the p27 gene (CDKN1B) but also enhances p27’s degradation through the upregulation of components of ubiquitin ligases complexes.
    [Show full text]
  • Regulatory Mechanisms of Tumor Suppressor P16<Sup>
    CURRENT TOPIC pubs.acs.org/biochemistry Regulatory Mechanisms of Tumor Suppressor P16INK4A and Their Relevance to Cancer † ‡ § || Junan Li,*, , Ming Jye Poi, and Ming-Daw Tsai † ‡ Division of Environmental Health Sciences, College of Public Health, and Comprehensive Cancer Center and § Department of Pharmacy, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, United States Genomics) Research Center and Institute of Biological Chemistry, Academia Sinica, Taiwan ABSTRACT: P16INK4A (also known as P16 and MTS1), a protein consisting exclusively of four ankyrin repeats, is recognized as a tumor suppressor mainly because of the prevalence of genetic inactivation of the p16INK4A (or CDKN2A) gene in virtually all types of human cancers. However, it has also been shown that an elevated level of expression (upregulation) of P16 is involved in cellular senescence, aging, and cancer progression, indicating that the regulation of P16 is critical for its function. Here, we discuss the regulatory mechanisms of P16 function at the DNA level, the transcription level, and the posttranscriptional level, as well as their implications for the structureÀfunction relationship of P16 and for human cancers. 16, also designated as MTS1 and P16INK4A, is one of the most ’ BASIC BIOCHEMICAL FEATURES OF P16 Pextensively studied proteins in the past decades because of its In 1993, a truncated version of the p16 cDNA gene was first critical roles in cell cycle progression, cellular senescence, and the fi 1À5 identi ed in a yeast two-hybrid screen for proteins that development of human cancers. At the G1-to-S transition, interact with human CDK4.12,13 The cDNA encoded a P16 specifically inhibits cyclin-dependent kinase 4 and 6 (CDK4 polypeptide of 148 amino acid residues with an estimated and CDK6, respectively)-mediated phosphorylation of pRb, the molecular mass of ∼16 kDa that negatively modulated the retinoblastoma susceptible gene product, thus sequestering E2F kinase activity of CDK4 (Figure 2A).
    [Show full text]
  • Differential Roles of P16 and P14 Genes in Prognosis of Oral
    414 Differential Roles of p16INK4A and p14ARF Genes in Prognosis of Oral Carcinoma R. Sailasree,1 A. Abhilash,1 K.M. Sathyan,1 K.R. Nalinakumari,2 Shaji Thomas,3 and S. Kannan1 1Laboratory of Cell Cycle Regulation and Molecular Oncology, Division of Cancer Research, 2Division of Dental Surgery, and 3Division of Surgical Oncology, Regional Cancer Center, Thiruvananthapuram, Kerala, India Abstract INK4A Background: Oral cancer patients are found to have observed in 30% of the cases. p16 deletion was poor clinical outcome and high disease recurrence associated with aggressive tumors, as evidenced by the rate, in spite of an aggressive treatment regimen. The nodal involvement of the disease. Low or absence of inactivation of INK4A/ARF loci is reported to be second p16INK4A protein adversely affected the initial treat- INK4A to p53 inactivation in human cancers. The purpose of ment response. Promoter methylation of p16 was this study was to assess the prognostic significance of associated with increased disease recurrence and acts the molecular aberrations in the INK4A locus for as an independent predictor for worse prognosis. ARF effective identification of aggressive oral carcinoma Surprisingly, p14 methylation associated with cases needing alternate therapy. lower recurrence rate in oral cancer patients with a Materials and Methods: The study composed of 116 good clinical outcome. Overall survival of these patients freshly diagnosed with oral carcinoma. The patients was associated with tumor size, nodal disease, INK4A genetic and epigenetic status of the p16 and and p16INK4A protein expression pattern. Our results ARF INK4A ARF p14 genes was evaluated. The relation between indicate that p16 and p14 alterations constitute these genic alterations and different treatment end a major molecular abnormality in oral cancer cases.
    [Show full text]
  • The MLL Fusion Gene, MLL-AF4, Regulates Cyclin-Dependent Kinase Inhibitor CDKN1B (P27kip1) Expression
    The MLL fusion gene, MLL-AF4, regulates cyclin-dependent kinase inhibitor CDKN1B (p27kip1) expression Zhen-Biao Xia, Relja Popovic, Jing Chen, Catherine Theisler, Tara Stuart, Donna A. Santillan, Frank Erfurth, Manuel O. Diaz, and Nancy J. Zeleznik-Le* Department of Medicine, Molecular Biology Program, and Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL 60153 Communicated by Janet D. Rowley, University of Chicago Medical Center, Chicago, IL, July 29, 2005 (received for review December 2, 2004) MLL, involved in many chromosomal translocations associated Recent studies suggest some potential mechanisms of MLL with acute myeloid and lymphoid leukemia, has >50 known fusion protein leukemogenesis. For example, fusion partner partner genes with which it is able to form in-frame fusions. dimerization domains and͞or activation domains fused to MLL Characterizing important downstream target genes of MLL and of can aberrantly activate downstream targets such as HOX genes MLL fusion proteins may provide rational therapeutic strategies for and contribute to cell transformation (13, 14). This regulation is the treatment of MLL-associated leukemia. We explored down- mediated at the level of target gene transcription. There is very stream target genes of the most prevalent MLL fusion protein, strict regulation of HOX gene expression during hematopoiesis, MLL-AF4. To this end, we developed inducible MLL-AF4 fusion cell therefore misregulated expression of these genes is likely im- lines in different backgrounds. Overexpression of MLL-AF4 does portant in MLL leukemogenesis. not lead to increased proliferation in either cell line, but rather, cell During normal hematopoiesis, a tight balance is required be- growth was slowed compared with similar cell lines inducibly tween levels of mostly quiescent stem cells that can renew the expressing truncated MLL.
    [Show full text]
  • Potential Synergistic Effect with Altered P53 Protein on Proliferative Activity
    ICANCERRESEARCH56,5557—5562,December15, 19961 Advances in Brief Altered @16INK4andRetinoblastoma Protein Status in Non..Small Cell Lung Cancer: Potential Synergistic Effect with Altered p53 Protein on Proliferative Activity Ichiro Kinoshita, Hirotoshi Dosaka.Akita,' Takayuki Mishina, Kenji Aide, Motoi Nishi, Hiromitsu Hiroumi, Fumihiro Hommura, and Yoshikazu Kawakami First Department of Medicine, Hokkaido University School of Medicine Ii. K., H. D-A.. T. M., K. A., H. H., F. H., Y. K.J, and Department of Public Health, Sapporo Medical University School of Medicine [M. N.], Sapporo 060. Japan Abstract (4, 6), which is supported by observation of an inverse correlation between alteration of both proteins in several types of tumors (7—13). p16@―4protein (pl6) and retinoblastoma protein (pith), like p53 pro In NSCLCs, whereas the RB gene is shown to be inactivated in Win, are Important tumor suppressors that regulate the cell cycle. We 6—32%of the tumors (14—18),the frequency of alteration involving immunohistochemically examined fresh-frozen specimens of 114 resected non-small cell lung cancers (NSCLCs) for loss of p16 and pRB expression, the CDKN2 gene is controversial. Of NSCLC cell lines, homozygous together with aberrant accumulation of p53 proteIn and the proliferative deletion of the CDKN2 gene is observed in 20—50% and point activity determined by the Ki-67 Index. Three pith-positive tumors were mutation in 6—21% (2, 3, 10—12, 19—22). Recent reports showed uninterpretable for p16 status. Of the remaining 111 tumors, 30 (27%) DNA hypermethylation with CDKN2 gene silencing in about 30% of lacked p16 expression, and 10 (9%) lost pith expression.
    [Show full text]